The present invention relates to chroman or thiochroman derivatives having anti-estrogenic activity.
In treating diseases caused by abnormal tissue growth that is dependent upon a certain sexual steroidal hormone such as estrogen, it is highly important to significantly inhibit, more preferably completely eliminate, the effect induced by the hormone. For this purpose, it is desirable to reduce the level of hormone capable of acting on the steroidal hormone receptor site. For instance, anti-estrogenic agents are commonly administered for alternative or combination therapy to limit the production of estrogen to the amount less than required to activate the receptor site. However, such conventional technique for blocking estrogen production could not sufficiently inhibit the effect induced through the estrogen receptor. Practically, even when estrogen is completely absent, some of the receptors may be activated. It was therefore considered that estrogen antagonists could provide better therapeutic effect in comparison to the technique for blocking only the production of sexual steroidal hormone. Thus, numerous estrogen antagonists have been developed. For example, many patent publications including U.S. Pat. Nos. 4,760,061, 4,732,912, 4,904,661, 5,395,842 and WO 96/22092 disclose various anti-estrogenic compounds. Sometimes, however, prior art antagonists may themselves act as agonists, and therefore activate rather than block the receptor. For example, Tamoxifen has been most widely used as an anti-estrogenic agent. However, this agent has a disadvantage that it exhibits estrogenic activity in some organs (see, M. Harper and A. Walpole, J. Reprod. Fertile., 1967, 13, 101).
As another non-steroidal anti-estrogenic compound, WO 93/10741 discloses a benzopyran derivative having an aminoethoxyphenyl substituent(s) (Endorecherche), the typical compound of which is EM-343 having the following structure: 
Said compound also has the agonistic effect. It is therefore required to develop an anti-estrogenic compound which is substantially or completely free of agonistic effect and which can effectively block the estrogen receptor.
In addition, it has been known that 7xcex1-substituted derivatives of estradiol, for example, 7xcex1-(CH2)10CONMeBu derivatives, are steroidal anti-estrogenic agents without agonistic effect (see, EP-A 0138504, U.S. Pat. No. 4,659,516). Further, an estradiol derivative having a 7xcex1-(CH2)9SOC5H6F5 substituent has also been disclosed (see, Wakeling et al., Cancer Res., 1991, 51, 3867).
Non-steroidal anti-estrogenic agents without agonistic effect have been first reported by Wakeling et al. in 1987 (see, A. Wakeling and Bowler, J. Endocrinol., 1987, 112, R7). Meanwhile, U.S. Pat. No. 4,904,661 discloses phenol derivatives having anti-estrogenic activity. These phenol derivatives generally have a naphthalene scaffold and include, typically, the following compounds: 
Some chroman and thiochroman derivatives have been reported as anti-estrogenic compounds having no agonistic effect (WO 98/25916). Although the existing anti-estrogenic compounds having no agonistic effect show a substantial therapeutic effect when administered via intravenous or subcutaneous injection, they show a highly reduced therapeutic effect when administered orally, probably due to their low bioavailability by oral route, etc. Therefore, for convenience""s sake in the case of administration, it is desired to develop anti-estrogenic compounds which show a sufficient effect when administered orally and at the same time have no agonistic effect.
The object of the present invention is to provide chroman or thiochroman derivatives which have anti-estrogenic activity and are advantageous in pharmaceutical use.
The present inventors researched anti-estrogenic activity of compounds having various structures. As a result, we have found that chroman or thiochroman derivatives of general formula (1) could show a good anti-estrogenic activity in substantial absence of agonistic effect and that they provided a sufficiently high activity even when administered orally. The present invention has been accomplished on the basis of this finding.
Namely, the present invention provides a compound having the following general formula (1): 
in which
R1 represents a hydrogen atom or a salt-forming metal;
R2 represents a linear or branched C3-C5 perhalogenoalkyl group or a group of the following general formula (2): 
in which
each of R5 and R6 represents a linear or branched C1-C3 perhalogenoalkyl group;
each of R3 and R4 independently represents a hydrogen atom, an optionally substituted linear or branched C1-C3 alkyl group, an acyl group or a salt-forming metal;
X represents an oxygen atom or a sulfur atom;
m represents an integer of 2 to 14; and
n represents an integer of 0 to 8;
or enantiomers of the compound, or hydrates or pharmaceutically acceptable salts of the compound or its enantiomers.
In addition, the present invention provides a pharmaceutical composition comprising a compound of general formula (1) as an active ingredient. Further, the present invention provides an anti-estrogenic pharmaceutical composition comprising the above compound as an active ingredient. The present invention also provides a therapeutic agent for breast cancer comprising the above compound as an active ingredient.
Salt-forming metals as R1 include, but are not limited to, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, rare earth metals such as cerium and samarium, as well as zinc and tin. Among these, preferred are alkali metals and alkaline earth metals, particularly sodium, potassium and calcium.
R1 may preferably be a hydrogen atom, an alkali metal or an alkaline earth metal.
Halogens in the linear or branched C3-C5 perhalogenoalkyl groups as R2 include fluorine, chlorine, bromine and iodine, with fluorine being preferred. Alkyls in the linear or branched C3-C5 perhalogenoalkyl groups under consideration include, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and 1-ethylpropyl. Preferred are linear or branched C3-C4 alkyls, e.g., n-propyl and n-butyl.
Examples of the linear or branched C3-C5 perhalogenoalkyl group as R2 include the above-listed linear or branched C3-C5 alkyl groups, provided that they are perhalogenated, preferably perfluorinated, for example, perfluoro-n-propyl, perfluoro-n-butyl and perfluoro-n-pentyl. More specifically, a perfluoro-n-butyl group is preferred.
In the case where R2 is a group of general formula (2), halogens in the linear or branched C1-C3 perhalogenoalkyl groups as R5 and R6 include fluorine, chlorine, bromine and iodine, with fluorine being preferred. Alkyls in the linear or branched C1-C3 perhalogenoalkyl groups under consideration include, methyl, ethyl, n-propyl and i-propyl, with methyl being preferred.
In the case where R2 is a group of general formula (2), examples of the linear or branched C1-C3 perhalogenoalkyl group as R5 and R6 include the above-listed linear or branched C1-C3 alkyl groups, provided that they are perhalogenated, preferably perfluorinated. Further, perhalogenated C1 alkyl groups are preferred and a perfluorinated group is particularly preferred. More specifically, a perfluoromethyl group is preferred.
A group of general formula (2) as R2 is preferably a 1,1,1,3,3,3-hexafluoroisopropyl group.
Having the definition given above, R2 is preferably a perfluoro-n-butyl group.
Alkyls in the optionally substituted linear or branched C1-C3 alkyl groups as R3 and R4 include, but are not limited to, methyl, ethyl, n-propyl and i-propyl.
Substituents on the optionally substituted linear or branched C1-C3 alkyl groups as R3 and R4 include, an alkoxy group having a linear or branched C1-C5 alkyl as its alkyl moiety and a hydroxyl group, more specifically a methoxy group.
Examples of the optionally substituted linear or branched C1-C3 alkyl group as R3 and R4 include the above-listed alkyl groups, provided that they may be substituted with the above-listed substituents. Specific examples of the substituted alkyl group include a methoxymethyl group.
Examples of the acyl group as R3 and R4 include, an acetyl group, a benzoyl group and a pivaloyl group.
Salt-forming metals as R3 and R4 include, independently, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, rare earth metals such as cerium and samarium, as well as zinc and tin. Among these, preferred are alkali metals and alkaline earth metals, particularly sodium, potassium and calcium.
Preferably, R3 and R4 are independently a hydrogen atom or a salt-forming metal.
In a suitable combination of R1, R3 and R4, at least one or all of them may be a hydrogen atom and the remainder may be a salt-forming metal. Examples of such combination include the following: a combination where R1, R3 and R4 are each a hydrogen atom; a combination where R1 is a salt-forming metal (e.g., an alkali metal such as sodium) and R3 and R4 are each a hydrogen atom; and a combination where R1, R3 and R4 are each a salt-forming metal (e.g., an alkali metal such as sodium).
X may preferably be an oxygen atom or a sulfur atom.
m may preferably be an integer of 6 to 10, particularly 8 or 9.
n may preferably be an integer of 0 to 8, particularly 2 to 4.
Compounds of general formula (1) have enantiomers. All individual enantiomers and mixtures thereof are intended to be within the scope of the present invention. Among the enantiomers, preferred are compounds where the configuration of 3- and 4-position chiral carbons in the parent scaffold (i.e., chroman or thiochroman ring) in general formula (1) is (3RS,4RS), (3R,4R) or (3S,4S). Also compounds having R- or S-configuration at the carbon to which the carboxylic acid or its metal salt is bonded, wherein said carbon is the carbon on the side chain which is bonded to 4-position of the parent scaffold (i.e., chroman or thiochroman ring) and mixtures of such compounds at any ratio are preferable.
Among compounds of general formula (1), preferred are those compounds in which R1 is a hydrogen atom, an alkali metal or an alkaline earth metal; R2 is a perfluoro-n-propyl group, a perfluoro-n-butyl group or a 1,1,1,3,3,3-hexafluoroisopropyl group; each of R3 and R4 is independently a hydrogen atom, an alkali metal or an alkaline earth metal; X is an oxygen atom or a sulfur atom; m is an integer of 8 or 9; and n is an integer of 2 to 4. Particularly preferred are compounds in which:
a) R1 is a hydrogen atom, R2 is a perfluoro-n-butyl group, R3 is a hydrogen atom, R4 is a hydrogen atom, X is a sulfur atom, m is 8, and n is 2;
b) R1 is a hydrogen atom, R2 is a perfluoro-n-butyl group, R3 is a hydrogen atom, R4 is a hydrogen atom, X is a sulfur atom, m is 8, and n is 3;
c) R1 is a hydrogen atom, R2 is a perfluoro-n-butyl group, R3 is a hydrogen atom, R4 is a hydrogen atom, X is a sulfur atom, m is 8, and n is 4;
d) R1 is a hydrogen atom, R2 is a perfluoro-n-butyl group, R3 is a hydrogen atom, R4 is a hydrogen atom, X is a sulfur atom, m is 9, and n is 2;
e) R1 is a hydrogen atom, R2 is a perfluoro-n-butyl group, R3 is a hydrogen atom, R4 is a hydrogen atom, X is a sulfur atom, m is 9, and n is 3;
f) R1 is a hydrogen atom, R2 is a perfluoro-n-butyl group, R3 is a hydrogen atom, R4 is a hydrogen atom, X is an oxygen atom, m is 8, and n is 2;
g) R1 is a hydrogen atom, R2 is a perfluoro-n-butyl group, R3 is a hydrogen atom, R4 is a hydrogen atom, X is an oxygen atom, m is 9, and n is 2;
h) R1 is a hydrogen atom, R2 is a perfluoro-n-butyl group, R3 is a hydrogen atom, R4 is a hydrogen atom, X is an oxygen atom, m is 8, and n is 3;
i) R1 is a hydrogen atom, R2 is a perfluoro-n-butyl group, R3 is a hydrogen atom, R4 is a hydrogen atom, X is an oxygen atom, m is 9, and n is 3;
j) R1 is a sodium atom, R2 is a perfluoro-n-butyl group, R3 is a hydrogen atom, R4 is a hydrogen atom, X is a sulfur atom, m is 8, and n is 2; or
k) R1 is a sodium atom, R2 is a perfluoro-n-butyl group, R3 is a hydrogen atom, R4 is a hydrogen atom, X is an oxygen atom, m is 9, and n is 2.
The compounds of the present invention may be obtained as hydrates.
As typical examples of these compounds, the following compounds can be mentioned:
10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-thiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoic acid;
10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-thiochroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoic acid;
10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-thiochroman-4-yl]-2-(5,5,6,6,7,7,8,8,8-nonafluorooctyl)decanoic acid;
11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-thiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoic acid;
11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-thiochroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)undecanoic acid;
10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-chroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoic acid;
11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-chroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoic acid;
10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-chroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoic acid;
11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-chroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)undecanoic acid;
sodium 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoate; and
sodium 11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoate.
As an optically active compound of general formula (1) that has chiral carbons at positions 3 and 4 of the parent scaffold and at xcex1-position to the carboxyl group of the side chain, each of the compounds represented by Peaks 1 and 2 in Examples 19, 21, 24 and 26 stated below is preferred.
Pharmaceutically acceptable salts include, the above-mentioned metal salts, for example, sodium, potassium and calcium salts. Such metal salts may be formed with a carboxyl group and/or a phenolic hydroxyl group in the compound of the present invention.
The compound of general formula (1) may be administered as a pharmaceutical composition in any dosage form suitable for the intended route of administration, in combination with one or more pharmaceutically acceptable diluents, wetting agents, emulsifiers, dispersants, auxiliary agents, preservatives, buffers, binders, stabilizers and the like. The compound and composition may be administered parenterally or orally.
The dose of the compound can be suitably determined according to the physique, age and physical condition of a patient, severity of the disease to be treated, elapsed time after onset of the disease, etc. For example, the compound is generally used in an amount of 0.1 to 500 mg/day when orally administered and in an amount of 1 to 1000 mg/month when parenterally administered (by intravenous, intramuscular, or subcutaneous route) for adult patient.
The compound of general formula (1) can be prepared according to any one of the following Reaction Schemes 1 to 10 (Processes 1 to 10). 
In the above Reaction Scheme 1 (Process 1), R2, X, m and n are as defined above in general formula (1); each of R11, R12 and R13 represents a protecting group; each of L1 and L2 represents a leaving group; and m1 equals m-2. 
In the above Reaction Scheme 2 (Process 2), R2, X, m and n are as defined above in general formula (1); and R11 represents a protecting group. 
In the above Reaction Scheme 3 (Process 3), R2, X, m and n are as defined above in general formula (1); each of R11 and R13 represents a protecting group; and L1 represents a leaving group. 
In the above Reaction Scheme 4 (Process 4), R2, X, m and n are as defined above in general formula (1); each of R11 and R13 represents a protecting group; and m3+3 equals m. 
In the above Reaction Scheme 5 (Process 5), R2, X, m and n are as defined above in general formula (1); each of R11 and R13 represents a protecting group; and m3+3 equals m.
The preparation of the compounds according to the present invention will be illustrated below in more detail, in line with the above-mentioned reaction schemes.
[Process 1]
In the presence of a base (e.g., n-butyllithium, s-butyllithium, sodium hydride), compound (I) is reacted with alkyne (II) in an inert solvent (e.g., tetrahydrofuran, diethyl ether, dioxane, dichloromethane, chloroform, preferably tetrahydrofuran or dioxane) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from xe2x88x9278xc2x0 C. to room temperature, to give compound (III).
In the presence of a Lewis acid such as zinc iodide, compound (III) is reduced with sodium cyanoborohydride (NaBH3CN) in an inert solvent (e.g., tetrahydrofuran, diethyl ether, dioxane, dichloromethane, dichloroethane or chloroform, preferably dichloroethane) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to room temperature, to give compound (IV).
Using a catalyst (e.g., palladium on activated carbon, palladium hydroxide, platinum oxide), compound (IV) is hydrogenated in an inert solvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, preferably tetrahydrofuran, ethyl acetate) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at room temperature, to give compound (V). Compound (V) can be directly prepared from compound (III) through hydrogenation using a catalyst (e.g., palladium on activated carbon, palladium hydroxide or platinum oxide) in an inert solvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, preferably tetrahydrofuran, ethyl acetate) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at room temperature.
Compound (V) is subjected to deprotection of the alcoholic hydroxyl group in an inert solvent to give compound (VI).
In the presence of a base (e.g., triethylamine or pyridine), compound (VI) is treated with methanesulfonyl chloride or p-toluenesulfonyl chloride in an inert solvent (e.g., tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably dichloromethane) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at room temperature, to convert (CH2)mOH in compound (VI) into (CH2)mxe2x80x94Oxe2x80x94SO2CH3 or (CH2)mxe2x80x94SO2xe2x80x94C6H4xe2x80x94pxe2x80x94CH3. The compound thus obtained is then treated with a metal halide (e.g., sodium iodide or potassium iodide) in an inert solvent (e.g., acetone, tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably acetone) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (VII).
In the presence of a base (e.g., sodium hydride, sodium hydroxide or potassium t-butoxide), compound (VII) is reacted with a malonic ester of formula (VIII) (e.g., diethyl malonate or dimethyl malonate) in an inert solvent (e.g., tetrahydrofuran, dioxane, dimethylformamide, dichloromethane, dichloroethane or chloroform, preferably tetrahydrofuran) at a temperature ranging from room temperature to the boiling point of the reaction mixture to give compound (IX).
In the presence of a base (e.g., sodium hydride, sodium hydroxide or potassium t-butoxide), compound (IX) is reacted with an alkylating agent of formula (X) in an inert solvent (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethylformamide, dichloromethane, dichloroethane or chloroform, preferably tetrahydrofuran) at a temperature ranging from room temperature to the boiling point of the reaction mixture to give compound (XI).
Compound (XI) is treated with sodium hydroxide or potassium hydroxide in a solvent (e.g., water, ethanol, methanol, a water/ethanol mixture or a water/methanol mixture) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (XII).
In a solvent (e.g., dimethyl sulfoxide, dimethylformamide, benzene, toluene, xylene, dioxane or tetrahydrofuran) and, if necessary, in the presence of an acid (e.g., hydrogen chloride, sulfuric acid or p-toluenesulfonic acid), compound (XII) is heated to a temperature ranging from 50xc2x0 C. to the boiling point of the reaction mixture to give compound (XIII).
Next, compound (XIII) is subjected to deprotection of the phenolic hydroxyl group to give compound (XIV).
[Process 2]
Compound (XIV) may also be synthesized from compound (XII) in the following manner. A procedure analogous to Process 1 is repeated until compound (XII) is prepared.
Compound (XII) is subjected to deprotection of the phenolic hydroxyl group to give compound (XV).
In a solvent (e.g., dimethyl sulfoxide, dimethylformamide, benzene, toluene, xylene, dioxane or tetrahydrofuran) and, if necessary, in the presence of an acid (e.g., hydrogen chloride, sulfuric acid or p-toluenesulfonic acid), compound (XV) is heated to a temperature ranging from 50xc2x0 C. to the boiling point of the reaction mixture to give compound (XIV).
[Process 3]
Compound (XIV) can also be prepared from compound (VII) in the following manner.
In the presence of a base (e.g., sodium hydride, sodium hydroxide or potassium t-butoxide), compound (VII) is reacted with compound (XVI) in an inert solvent (e.g., tetrahydrofuran, dioxane, dimethylformamide, dichloromethane, dichloroethane or chloroform, preferably tetrahydrofuran) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture to give compound (XI).
Compound (XI) is converted into compound (XIV) as in Process 1 or 2.
[Process 4]
Compound (XIV) may also be prepared in the following manner.
In the presence of a catalyst such as benzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound (XVII) is reacted with compound (XVIII) in a solvent (e.g., methylene chloride, chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (XIX).
Using a catalyst (e.g., palladium on activated carbon, palladium hydroxide, platinum oxide or Wilkinson""s catalyst), compound (XIX) is hydrogenated in an inert solvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane or benzene) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at room temperature, to give compound (XX).
Compound (XX) is converted into compound (XIV) as in Process 1 or 2 where compound (XI) is converted into compound (XIV).
[Process 5]
Further, compound (XIV) may also be prepared in the following manner.
In the presence of a catalyst such as benzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound (XVII) is reacted with compound (XXI) in a solvent (e.g., methylene chloride, chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (XXII).
Using a catalyst (e.g., palladium on activated carbon, palladium hydroxide, platinum oxide or Wilkinson""s catalyst), compound (XXII) is hydrogenated in an inert solvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, dichloroethane or benzene) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at room temperature, to give compound (XXIII).
Compound (XXIII), which is identical with compound (XI) in Process 1, is converted into compound (XIV) as in Process 1 or 2 where compound (XI) is converted into compound (XIV).
Compound (XVII) used in Processes 4 and 5 can be prepared by either Process 6 or 7 shown below. 
In the above Reaction Scheme 6 (Process 6), X is as defined above in general formula (1); and R11 represents a protecting group. 
In the above Reaction Scheme 7 (Process 7), X is as defined above in general formula (1); R11 represents a protecting group; and L3 represents a leaving group.
[Process 6]
Preparation of Compound (XVII)-Part I
Compound (I) is reduced with lithium aluminum hydride or diisobutylaluminum hydride in an inert solvent (e.g., diethyl ether, benzene, toluene, xylene, dioxane or tetrahydrofuran) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture to give compound (XXIV).
In the presence of a Lewis acid such as zinc iodide, compound (XXIV) is reacted with allyltrimethylsilane in an inert solvent (e.g., tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably dichloroethane) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to room temperature, to give compound (XVII).
[Process 7]
Preparation of Compound (XVII)-Part II
In the presence of anhydrous TBAF and, if necessary, accompanied by addition of HMPA, compound (XXV) is reacted with allyltrimethylsilane in an inert solvent (e.g., dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to room temperature, to give compound (XXVI).
In the presence of a base (e.g., lithium hexamethyl-disilazide, n-butyllithium, s-butyllithium, sodium hydride), compound (XXVI) is reacted with an alkylating agent (CH3-L3) in an inert solvent (e.g., tetrahydrofuran, ether, dioxane, dichloromethane, chloroform, preferably tetrahydrofuran or dioxane) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from xe2x88x9278xc2x0 C. to room temperature, to give compound (XXVII).
Compound (XXVII) is reduced with lithium aluminum hydride in an inert solvent (e.g., tetrahydrofuran, dioxane or diethyl ether) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture to give compound (XXVIII).
Compound (XXVIII) is reacted with diethyl azodicarboxylate and triphenylphosphine in an inert solvent (e.g., toluene, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, dichloroethane or chloroform) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to room temperature, to give compound (XVII).
Compound (XIV) given by the above Processes 1 to 5 may also be converted into a salt form because it has a carboxyl group. Pharmaceutically acceptable salts include, sodium, potassium and calcium salts. For example, a salt of compound (XIV) can be prepared as follows.
Sodium methoxide is added to compound (XIV) dissolved in an organic solvent (e.g., dry methanol) at an appropriate temperature, for example, at room temperature, and the resulting mixture is stirred for about 30 minutes to about 3 hours at the same temperature. After addition of an organic solvent such as dry diethyl ether, the reaction mixture is evaporated under reduced pressure to remove the solvent, thereby obtaining a salt of the compound.
The compound of the present invention exists as various enantiomers because it contains three asymmetric carbon atoms. To obtain a single stereoisomer, there are two techniques, one of which uses a chiral column to resolve a mixture of stereoisomers and the other involves asymmetric synthesis. The chiral column technique may be carried out using a column commercially available from DAICEL under the trade name of CHIRALPAK-OT(+), OP(+) or AD, or CHIRALCEL-OA, OB, OJ, OK, OC, OD, OF or OG, for example. Regarding asymmetric synthesis, the following will illustrate the asymmetric synthesis of the inventive compound with respect to an asymmetric carbon atom, to which a side chain carboxyl group is attached. 
[Process 8]
In the presence of a catalyst such as benzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound (XXIX) is reacted with compound (XXX) in a solvent (e.g., methylene chloride, chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (XXXI).
Compound (XXXI) is then subjected to the following reactions in the order stated, (a) reduction, deprotection and hydrolysis or (b) reduction, hydrolysis and deprotection, to give compound (XXXII).
(a) Reduction, Deprotection and Hydrolysis
1) Reduction
In the presence of a catalyst (e.g., palladium on activated carbon, palladium hydroxide, platinum oxide or Wilkinson""s catalyst), compound (XXXI) is hydrogenated in an inert solvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane or benzene) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably at room temperature, to give a reduction product.
2) Deprotection
Next, deprotection of the phenolic hydroxyl group is carried out to give a deprotected product.
3) Hydrolysis
By way of example, if R* is a group of formula (XXXVIII), the deprotected product is further treated with lithium hydroxide, sodium hydroxide, lithium hydroxide plus hydrogen peroxide, sodium hydroxide plus hydrogen peroxide, or tetrabutylammonium hydroxide plus hydrogen peroxide in a solvent (e.g., a tetrahydrofuran/water mixture, a diethyl ether/water mixture, a dioxane/water mixture, a methanol/water mixture, an ethanol/water mixture) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at room temperature, to give compound (XXXII).
(b) Reduction, Hydrolysis and Deprotection
1) Reduction
In the presence of a catalyst (e.g., palladium on activated carbon, palladium hydroxide, platinum oxide or Wilkinson""s catalyst), compound (XXXI) is hydrogenated in an inert solvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane or benzene) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably at room temperature, to give a reduction product.
2) Hydrolysis
By way of example, if R* is a group of formula (XXXVIII), the reduction product is further treated with lithium hydroxide, sodium hydroxide, lithium hydroxide plus hydrogen peroxide, sodium hydroxide plus hydrogen peroxide, or tetrabutylammonium hydroxide plus hydrogen peroxide in a solvent (e.g., a tetrahydrofuran/water mixture, a diethyl ether/water mixture, a dioxane/water mixture, a methanol/water mixture, an ethanol/water mixture) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at room temperature, to give a carboxylic acid.
3) Deprotection
Next, deprotection of the phenolic hydroxyl group is carried out to give compound (XXXII).
[Process 9]
In the presence of a catalyst such as benzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound (XXIX) is reacted with compound (XXXIII) in a solvent (e.g., methylene chloride, chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (XXXIV).
In the presence of a catalyst (e.g., palladium on activated carbon, palladium hydroxide, platinum oxide or Wilkinson""s catalyst), compound (XXXIV) is hydrogenated in an inert solvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane or benzene) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably at room temperature, to give a reduction product.
Next, deprotection of the phenolic hydroxyl group is carried out to give compound (XXXII).
The chiral olefins of formulae (XXX) and (XXXIII) used in the above Processes 8 and 9, respectively, may be synthesized as follows (Reaction Scheme 10). 
Examples of R* include: 
In the above Reaction Schemes 8, 9 and 10 (Processes 8, 9 and 10), R2, X, m and n are as defined above in general formula (1); R* represents a chiral auxiliary group; P represents a leaving group; L represents a leaving group; and m2 and m3 are integers that satisfy the relation m=m2+m3+2. The symbol R in formula (XXXIV) represents an alkyl group.
[Synthesis of Chiral Olefins]
In the presence of a base (e.g., lithium diisopropylamide, lithium hexamethyl-disilazide, sodium hexamethyl-disilazide, butyllithium) and HMPA, compound (XXXV) is reacted with R2(CH2)nxe2x80x94L in an inert solvent (e.g., tetrahydrofuran, toluene, diethyl ether, hexane, preferably tetrahydrofuran) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from xe2x88x9230xc2x0 C. to room temperature, to give compound (XXX).
Alternatively, in the presence of a base (e.g., lithium diisopropylamide, lithium hexamethyl-disilazide, sodium hexamethyl-disilazide, butyllithium) and HMPA, compound (XXXVI) is reacted with compound (XXXVII) in an inert solvent (e.g., tetrahydrofuran, toluene, diethyl ether, hexane, preferably tetrahydrofuran) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from xe2x88x9230xc2x0 C. to room temperature, to give compound (XXX).
In the presence of a nucleophilic reagent (e.g., lithium hydroxide plus hydrogen peroxide, lithium hydroxide, sodium methoxide, sodium thioethoxide) or an acid (e.g., hydrochloric acid, sulfuric acid), compound (XXX) is hydrolyzed in an inert solvent (e.g., methanol, ethanol, tetrahydrofuran, water, preferably a tetrahydrofuran/water mixture) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from room temperature to 50xc2x0 C., to convert the chiral auxiliary group R* into OH.
In the case where each of R3 and R4 is an acyl group or an alkyl group, the synthesis can be carried out according to Process 9.